Ashok E. Philip, Jacques H. Poupaert, Gwénaël Chevé, Giulio Muccioli, Didier Lambert, Christopher R. McCurdy
Structureactivity relationship of phenytoinergic antiepileptic drugs related to ameltolide
Med Chem Res (2007) 16:130135
Abstract Ameltolide shares with phenytoin and carbamazepine a common mode of
action involving interaction with central voltage-dependent sodium channels.
Ameltolide and structurally related benzanilides were subjected to molecular
modeling studies using both molecular mechanics (MM2, Amber96, and OPLS) and
semiempirical quantum mechanics (AM1, PM3, and PM3 Cosmo) to resolve a paradox:
while compounds with a phenytoin-like pharmacological profile possess a
CO-NH moiety in a cis-configuration, ameltolide was found via X-ray crystallography
to exist in the trans-configuration. Results obtained both by molecular
mechanics and semiempirical methods indicate that for ameltolide, the cis and
trans forms have similar energy content. Additional ab initio calculations performed
at 6
31G** gave a DE (Z E) on the order of 3 kcal/mol. In view of this small
energy difference between the cis and trans forms, it is conceivable that these
benzanilides
bind to their biological target in their cis configuration, therefore assuming
a common structureactivity relationship with classical antiepileptic agents.